N-Aminoalkyl-4-anilino pyridines

ABSTRACT

IN WHICH R is hydrogen, halogen, in particular chlorine, a lower alkyl radical, preferably with C1-C4, a lower acyl radical, preferably with C1-C4, a trifluoromethyl radical, a nitro group, a primary, secondary or tertiary amino group, or a nitrile, carboxamide, carboxy or carbalkoxy group; M IS 1, 2 OR 3, THE SUBSTITUENT(S) R being substituted symmetrically or asymmetrically in the phenyl nucleus and, where m is 2 or 3, being the same or different; A is hydrogen or a methyl group; R1 is an alkyl radical with C1-C4; R2 is an alkyl radical with C1-C4, the same as or different from R1 or R1 and R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring which may contain 1 or 2 additional hetero atoms, such as nitrogen, oxygen or sulphur, this heterocyclic group preferably being a substituted or unsubstituted morpholino group.   Novel N-amino-substituted 4-anilinopyridines are provided which have useful central nervous system activity particularly as excitants and anti-depressants. There are also disclosed pharmaceutical compositions containing the novel compounds and methods for making such compounds, the compounds having the formula:

United States Patent [1 1 Delarue et al.

1 N-AMINOALKYL-4-ANILINO PYRIDINES [75] Inventors: Jean-Louis Delarue; Albert Debarge,

both of Paris, France [73] Assignee: Merrell Toraude, Paris, France [22] Filed: Jan. 27, 1972 [21] Appl. No.: 221,382

Related US. Application Data [62] Division of Ser. No. 720,474, April 11, 1968,

abandoned,

[52] US. Cl. ..260/247.5 G; 2 60/268 H; 260/293.69; 260/296 R; 424/248 51 Int. cu 0071) 295/12 [58] Field of Search.. 260/296 R, 247.5 R, 247.5 G, 260/293.69, 268 H [56] References Cited UNITED STATES PATENTS 2,784,195 3/1957 Burtner 260/296 R 2,785,172 3/1957 Burtner 260/296 R 2,785,173 3/1957 Burtner 260/296 R 2,802,008 8/1957 Burtner 260/296 R Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or Firm-William J. Stein; Eugene O. Retter; George W. Rauchfuss, Jr.

[ Dec. 23, 1975 N N l r CH-A I C=Y R R I2 in which R is hydrogen, halogen, in particular chlorine, a lower alkyl radical, preferably with C -C a lower acyl radical, preferably with C -C a trifluoromethyl radical, a nitro group, a primary, secondary or tertiary amino group, or a nitrile, carboxamide, carboxy or carbalkoxy group;

in is 1, 2 or 3, the substituent(s) R being substituted symmetrically or asymmetrically in the phenyl nucleus and, where m is 2 or 3, being the same or different;

A is hydrogen or a methyl group;

R is an alkyl radical with C -C R is an alkyl radical with C -C the same as or different from R or R and R together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring which may contain 1 or 2 additional hetero atoms, such as nitrogen, oxygen or sulphur, this heterocyclic group preferablyv being a substituted or unsubstituted morpholino group.

7 Claims, N0 Drawings This is a division of application Ser. No. 720,474 filed on Apr. ll, 1968, now abandoned,

This invention is concerned with novel N'-animo-substituted 4'-anilino-pyridines, with a method for their preparation and with pharmaceutical compositions containing them. I

We have found that a class of novel N-amino-substituted 4-anilino-pyridines have valuable central nervous system activity, more particularly excitant and anti-depressive activity; these compounds have the formula:

in which:

R is hydrogen, halogen, in particular chlorine, a lower alkyl radical, preferably with C -C a lower acyl radical, preferably with C -C a trifluoromethyl radical, a nitro group, a primary, secondary or tertiary amino group, or a nitrile, carboxamide, carboxy or carbalkoxy group; m is l, 2 or 3, the substituent(s) R being substituted symmetrically or asymmetrically-in the phenyl nucleus and, where m is 2 or 3, being the same ordifferent; A is hydrogen oramethyl group; h Y is an oxygen atomtor two hydrogen atoms; R is an alkyl radical with C -C R is an alkyl radical with C C the same as or different from R or a heterocycle-methyl radical, preferably alpha-furyl-methyl, or R and R together with the nitrogen atom to which they are attached form a 5- or'-membered heterocyclic ring which may contain 1 or 2 additional hetero atoms, such as nitrogen, oxygen or sulphur, this heterocyclic group preferably being a substituted or unsubstituted morpholino group. The same-pharmacological activity is shown by the acid addition saltsof the compounds of formula I.

The compounds of formula I and their acid addition salts are novel compounds and constitute one aspect of the present invention.

The compounds of formula I-in which Y is two hydrogen atoms can be prepared by reacting a 4-anilino-pyridine of the formula:

(II) a in which R and m havevthe above-stated meanings, with an w-haloalkyl amine of the formula:

in which X is a halogen atom, preferably chlorine, and A, R and R have the above-stated meanings, in the presence of an acid binding agent, preferably sodium amide, and an inert organic solvent, preferably dimethyl formamide.

The product of the reaction is usually distilled under reduced pressure and obtained in the crystalline state in the form of a salt by combination with an organic acid.

The compounds of formula I in which Y is an oxygen atom can be prepared by a process which comprises (i) condensing a 4-anilino-pyridine of formula II with acrylonitrile-to obtain a nitrile of the formula:

in which R- and m have the above-stated meanings, (ii) hydrolysin'g the nitrile of formula IV to convert the nitrile function into a carboxylic acid function, thus obtaining an acid of the formula:

and (iii) condensing the latter with an amine of the formula:

in which R and R have the above-stated meanings.

The present invention also comprises a pharmaceutical composition comprising one or more compounds of formula I or acid addition salts thereof and an inert, physiologically acceptable carrier.

In order that the invention may be more fully understood, the following examples are given by way of illustration only:

EXAMPLE 1 5.6 g of 4-anilino-pyridine (1/30 mol) in 80 cc of anhydrous dimethyl formamide were poured into a 250 cc three-necked flask provided with a mechanical stirrer and a condenser equipped with a moisture guard. The mixture was warmed until a clear solution was obtained. 1.7 g of sodium amide (1/30 mol. 30%) were then added in a single addition and the whole was left for onehourat ambient temperature, 4.8 g of lchloro-35dimethylamino-propane (1/30 mol. 20%) were then added. After 8 hours a t ambient temperature, the whiole was heated to 50C for 24 hours. The mixture was filtered throughfilter paper to remove the sodium chloride formed'and the excess amide. The clear dimethyl formamide solution was concentrated and the residue was dissolved in four volumes of ether. The ethereal solution was placed in a refrigerator at C for a little time. An insoluble product mainly consistingof thestarting materialseparated. The ethereal solution .was filtered and concentrated. The residual oil was. :list illedunder vacuum. B.p. 190C at 0.05 mmHg.

The product was isolated in the. form of disalicylate. Melting point: 144C, recrystallised in isopropanol. Analysis: C n, 1'l -,l I O (mol. wt. 531.618)

1 C% H% N%- 1 0% Theoryi- 61:92 6.24 7.90 18.06 Found: 67.79 6.24 7.79 18.23

EXAMPLE 2 N"-[ 3 -morpholino-propy1]-N-[meta-chlorophenyl]-4- amino-pyridine 14 g of 4-(meta ehloroanilino)-pyridine (1/15 mol.) in cc of anhydrousdimethyl formamide were reacted as in Example 1 with 3.4 g of sodium amide Ill 5 mol. 30%) and 13 g of l-chloro-3-morpholino-pro- Theory: 63.20 5.63 6.91 5.83 18.41

Found: 63.05 5.45 6.82 5.85 18.45

EXAMPLE 3 N-(3 -N-morpholino-propyl )-N-( meta-t'rifluoromethylphenyl )-4-amino-pyridine .A solution of 23 g of 4-(m-trifluoromethyl-anilino)- pyridine (1/10 mole) in cc of anhydrous dimethylformamide was introduced into a 250 cc three-necked flask provided with a mechanical agitator and a condenser having a moisture trap. A clear'solution was obtained at ambient temperature. 5 g of sodium amide (30% excess) were then introduced in a single addition and the mixture was stirred at ambient temperature for 3 hours. 19.5 g of l-chloro-3-morpholino-propane (l/l0 mol 20% excess) were then added. After 8 hours at ambient temperature, the mixture was stirred for a further 32 hours at 60. The sodium chloride precipitate was separated. The dimethyl formamide was concentrated to give a syrupy oil. It was dissolved in 4volumes of ether and the ethereal solution was decanted and placed'in a refrigerator for 24 hours. A solid residue was separated, consisting mainly of the 4-anilino-pyridine starting material. The ethereal solution was concentrated, the residual oil was distilled at a pressure of 0.01 mm Hg and the middle fraction, which distilled at from 220 to 250 was taken. Weight --20 g (Yield -'55%). I

The disalicylate of N -(3'-N-morpholino-propyl)-N- (meta-trifluoromethyl-phenyl)-4-amino-pyridine was recrystallised from isopropanol; m.p. 128.

' 5 Analysis: C H N F O 641.656 -cc,anhydrous dimethyl formamide were reacted with 21.5 g of 1-chloro-2-methyl-3-morpholino-propane (3% H% N% m; (l/l0mol. in the presence of 5 g of sodium gheory: 61.77 5.34 6.55 8.88 1 "amide (1/10 mol. e rces's). The reaction was 6172 5 carried out under the same conditions of time and temperature as in Example I. Distillation of the final mixture yielded 17 "g of an oil boiling at 220230 to EXAMPLE J 0.05 mm .Hg. Yield: 50%. N-(2'-methyl-3 '-(N-morpholino')-propyl) N-(meta- The dimaleate of above product was crystallised from chlorophenyl)-4-amino-pyridine 1O acetone: 63.

f Analysis: c ,11 N c1 0 578.037

i C% H% N7 CW 07 N N Theory: 56.10 5.58 7.2 7 6.13 24.9 l v I I I A 15 Found: 55.94 5.6 1 6.93 5.74 24.31

1* I I (vi-CH EXAMPLE 5 43 CH 1 The com ounds of Examples 5 to 43 shown in Tables 1 2 p N 20 l to X below were prepared in a manner s1m1lar to that 1 described in Examples 1 to 4'; the compounds are indicated in each table according to the particular substitu- \0 tion in the phenyl ring of their structure and according to the group joined to the nitrogen atom of the anilino 1 425 group. Each table-alsoincludesadescription ofthe salt In a similar manner to the previous example; 20.5 g which was isolated, with its constants, melting point, of 4-(meta-chloro-anilino)-pyridine (1/10 mol.) in and analysis.

TABLEI Z Example N0. Salt m.p. of salt Analysis "C Theory Found /CH, 0:57.24 57.11 CH -Cl-l -CH N 5 fumarate 108 H: 5.72 6.24 cn N: 7.70 7.97 0129.32 27.73

Y I 1 c.6933 69.45 c11 -c11 -c112-11 6 salicylate 11; 6.52 6.65 N: 7.35 7.46 0:16.79 16.94

C H -CH CH N o 7 salicylate 132 52 6 .15 21 1 N: 7.32 7.25 019.52 19.94

C:68.92 68.81 CH -CH .CH,N s salilcylate 140 11; 6.32 6.31 N: 7.53 7.34 0117.21 17.47

TABLE 11 Z Example No. Salt m.p. of salt Analysis 1 "C Theory Found 'c11 069.30 69.22 CH CH 'CH N 9 salicylate H: 6.76 6.56 H. N:8.81" 8.74 0.15.10 15.31

cH. H. H.;N/' 10 Sauc 1m 159 51 27 1 213i r N: 7.17 7.12 0:16.39 16.42

TABLE II -c'ontinued Analysis d 996 n 0 w 767 F 6 4 W M m M67 T CHNO salic ylate salic ylate TABLE 111 Salt mlp. of salt Analysis Cs Theory Found Example No.

salicylate Cu -ca om- N salicylate salicylate salicylate C:69.08 H: 6.85 N: 7.32

sallcylate TABLE IV Example N0.

cH cH salicylate TABLE VI-continu e'd Salt m.p. of salt Analysis C Theory Found Example No.

malate salicylate TABLE VII 3 3 salicylate 34 saua 'me' TABLE VIII m.p. of salt Salt Example No.

salicylate TABLE X Cl I Z Example No. Salt m.p. of sal Analysis C 1 Theory Found C:59.81 59.38 CH,-CH Cl-l N\ O 43 disalicylate 162 H: 5.17 5.36 N: 6.54 6.25

Cl:ll.03

The following examples illustrate the preparation of compounds of formula I in which Y is an oxygen atom, these compounds being N-[3-(N-morpholino)-3'- oxo-propyl]-4-anilino-pyridines.

EXAMPLES 44 49 N 3 '-(N-morpholino)-3 -oxo-propyl]-N-(3 -chlorophenyl)-4-amino-pyridine (Example 44) and analogous compounds a. Preparation of 3-[N(3-chlorophenyl)-N-4- pyridino)-amino]-propionitrile (nitrile a) 70 g of 4-(meta-chloro-anilino)-pyridine in suspension in 200 cc of acrylonitrile and 4 of Dowex 2X Standard resin were placed in a flask provided with an agitator. The mixture was heated under refluxfor hours. The insoluble starting material dissolved during the course of the reaction. After cooling, the product crystallised from the reaction medium. After elimination of the resin by filtration, the product was recrystallised. A first, very pure, cropof crystals was obtained weighing 55 g, m.p. 120C (capillary tube); the mother liquor was evaporated to dryness under reduced pressure and the residue was recrystallised from benzene. A second crop weighing g was obtained, m.p. 120C. The yield was about 90%.

As the product can be recharged on the first mothe liquor which facilitates solubilisation of the starting material and increases the rate of the reaction it can be considered that, over a number of operations, the yield is nearly 100%.

In the same manner, starting from the corresponding 4-anilino-pyridines, the following intermediates were prepared:

3-[N-(3,5'-dichlorophenyl)-N-(4'-pyridino)-amino]- propionitrile, (nitrile b); m.p. 122C (capillary tube) 3-[N-(3-trifluoromethyl-pheny1)-N-(4'-pyridino)- amino]-propionitrile, (nitrile c); m.p. 93C (capillary tube).

b. Preparation of 3-[N-(3 ,5-dich1oro-phenyl)-N- (4-pyridino)-amino]-propanoic acidjfhydrochloride 25 g of nitrile b, described in (a) above, were added to 50 cc of 50% aqueous hydrochloric acid. The mixture was heated to reflux temperature for 40 hours. On cooling, the amino-acid hydrochloride formed, crystallised. The product was dried under a pressure of 0.01 mm Hg in the presence of caustic soda pellets and weighed 30 g. It was recrystallised in isopropanol after I filtration of the ammonium chloride; weight of recrystallised product 24 g, m.p. 210C (capillary tube).

In the same manner, using the corresponding nitriles, the following intermediates were prepared:

propanoic acid hydrochloride, acid 1); m.p. 110C (capillary tube) 3-[N-(3'-trifluoromethylphenyl)-N-(4-pyridino)- ..amino]-propanoic.aeidr hydrochloride, (acid 2 mp.

66C (capillary tube) formed. The reaction'mixture was left to "s'tandf'ofi 24 hours, then filtered, the methylene? chloride solutionacetate, m.p. C (capillary tube). I I,

Analysis: C% l-l% N% C1% 0% Theory: 61.91 5.61 8.66 7.31 16.43 Found: 62.11 5.64 8.81 7.22 16.56

Using the same procedure as described in Example 44, the compounds indicated in Table Xl were prepared; the Table shows, in addition to the structure of v the com poundsjthe melting point'of their salts and the results of their analysis.

TABLE x1 Example No. R R Z Salt m.p. of salt Analysis "C Theory Found C:63.34 63.25 H H: 5.90 5.92 45 Cl H CH CI-l CON o salicylate 131 N: 8.21 8.16 4 Cl:6.92 6.84 H :15.62 15.69

0.5792 57.80 46 c1 Cl CH2CH1CON o salicylate 162 H: 4.86 5.00 N: 8.10 7.92 Cl:l3.67 13.52 0.15.43 15.61

051.77 51.18 /CH3 11; 5.66 5.79 47 Cl Cl CH2-CH2CO-N o hydrochloride 178 N: 9.07 9.07 monohydrate Cl:22.98 23.15 H 010.37 10.36

C:60.34 60.15 48 c1= n c1-1, c1-1, co N o salicylate 158 1-1: 5.06 4.90 N: 8.12 8.01 1 F:ll.0l 10.88

cu C:6l.64 61.46 49 CF;. 11 cH,-cH, co-N o 3 salicylate 130 1115.54 5.65 N: 7.70 7.86

dose administered (5, 10, 30, 60 and 100 mg/kg of 55 body weight). The test enables the reaction of the animals to be evaluated by examining a series of characteristics (spontaneous activity, tremors, sensitivityto touch, sensitivity to pain, ataxia, and exophthalmos) which are classed from 0 to 8 or 4 to 8 according to the reaction being studied. The test alsogives an approximate value for LD 50.

The results are given in Table A below, which indicates the dose (in mg/kg of body weight) at which a given effect appears. 4

The LD 50 of the compounds studied are in the region of 80 mg/kg and in some cases are as high as l 10 mg/kg (compounds of Examples 3 and 40) and 125 mg/kg (Examples ll and 28). Some compounds are more toxic.

The compound of Example 39 has LD 50 of mg/kg The compound of Example 47 has LD 50 of 45 mg/kg The compound of Example 29 has LD 50 of 45 mg/kg The symptoms observed in the course of the behaviour study were unobtrusive and were only produced in the majority of cases with strong doses and immediately after injection. The overall picture of the activity of the various compounds can be summarised as follows:

The compound of Example 2 was slightly exitant as were those of Examples 29 and 48.

The compound of Example 3 caused rather marked excitation (irritability, Straub phenomenon) as did those of Examples 35, 37 and 42.

On the other hand, the compounds of Examples 4, 46, 47 and 49 were very slightly depressant and those of Examples 36, 40 and showed little or no activity.

TABLE A Compound of v Example 2 16 3 4 30- 40 29 Overall Predo- Some Rather Marked Rather Rather Slightly behavior minant excitant marked excita marked marked excitant excitant action excitation excitaexcitaaction tion tion tion LD5O 95 80- 110 80 80 l 1 0 45 in mg/kg (intravenous) Spontaneous or at 100 ,at 30 activiyr at 60 at 60 at 100 at 60 after inj.

rrita iit at 30 at l0 at-30 at 30 Sensitivity to 2 j j 2 touch Tremors/ at 60 at 100 at 60 at [0 at 30 at 100 at 30 Convulsions after inj. Ataxia at 60 at 60 at 100 4- at 30 after inj. Exophthalmos at 60 at 60 4- at 30 after inj. Straub 4- at 30 phenomenon after inj.

Compound of Example 35 36 37 39 41 42 v 45 46 47 48 49 Overall S k 1me Average Average Depress- Some Depress- Slightly Slightly Slightly Slightly w at behavior excitant activity Excitant activity ant excitant ant depressdepressdepressdepressaction ant ant ant ant LDSO 80 80 8O 25 80 80" 8O 8O 45 9O S0 [11 mouse in mg/kg (intravenous) Spontaneous slight slight slight at 60 slight activity at 60 at at 60 at 30 after at 60 at 60 \at 30 and 60 inj. lrritability slight slight Sensitivity at 60 ,at 30 at 60 at 30 ,at 60 at 60 to touch Tremors/ at 60 at 60 at 60 at 30 at 60 at 30 at 30 at 30 at 60 at 60 convulsions after after after after after and 60 after after after after inj. inj. inj. inj. inj. inj. inj. inj. inj. Ataxia at 30' at 30 at 60 30 at 30 at 60 at 60 at 30 +at 30 aT 60 at 60 after after after after after after after after after after after inj. inj. inj. inj. inj. inj. inj. inj. inj. inj. inj. Exophthalmos +at 60 at 60 after after inj. inj. Straub at 60 at 60 at 60 at 60 at 60 at 60 phenomenon after after after after inj. inj. inj. inj.,

B. Exploratory tests of psychotropic activity In order to demonstrate potentiation, the barbiturate The tests on the central nervous system were made 45 (penthiobarbital) was injected intraperitoneally in on groups of 10 male mice; the amounts injected were a greater or lesser fraction of the LD 50, depending on the tests. I

The results are shown as a percentage of the animals which react, expressed as a function of time. They are 5 given in Table 2 below and classified as follows:

O no reaction i doubtful reaction positive reaction.

The arrows or indicate an increase or decrease and the amount of the effect as percentage.

l, The activity of the compounds according to the invention has been evaluated by means of the Rota-rod test (Tripod, J. and coll., Arch. int. Pharmac0dyn., 1957, H2, 319); the chimney test (Boissier, JR. and coll., Medicina Exper., 1960, 3, No. l, 81), and the traction rest (Courvoisier S.; J Clin. Exp. Psychopath, 1956, 17, -37). A

The compounds according to the invention which appeared interesting from this screening were then, used in the following tests: 9

2. Potentiation of or antag cosis onism to barbiturate nardoses sufficient to cause short sleep and varying between 40 and 50 mg/kg according to the batches of mice, 1 5, or 45 minutes after the compound under test. ln'order to study antagonism, 55 mg/kg of penthi- 0 obarbital was injected, causing all the animals to sleep.

The length of sleep was noted; the criterion of sleep is the loss of the tredressement reflex. The results are shown as the percentage of animals asleep, expressed as a function of time.

The compounds under study were found not to potentiate or antagonise sleep produced by barbiturates. The compounds of Examples 3, 4 and 35, however, markedly-potentiate narcosis, the compound of Example being the most active at a dose of mg/kg.

3. Potentiation of chloral narcosis The method used is described by BUCHEL, L. and coll. (Therapie 1962, XVII, pp. 1053-1094). 15 or 20 Minutes after the compound under test had been intraperitoneally injected; chloral hydrate was intraperitoneally injected into batches of 10 mice in dosesof 325 mg/kg), (causing all the control animals to go to sleep). The length of sleep was noted in the same way as for penthiobarbital narcosis and the results were shown as 21 the percentage of animals asleep, expressed as a function of time.

This test confirms the results of the tests for the potentiation of penthiobarbi'tal narcosis. The compounds in Examples 3 and 4 potentiate the narcosis.

4. Potentiation or antagonism of the effects of pentetrazol 30 to 45 Minutes after the compound under test had been administered, a convulsive, non-mortal dose of pentetrazol (30 to 45 mg/kg) was intravenously injected when potentiation was required, or a nearly 100% lethal dose (60 mg/kg) if it was desired to demonstrate an antagonistic effect. The results comprise 3 percentages: percent of tremors, percent of tits and percent of deaths.

None of the products tested is antagonistic, but most potentiate the effects of pentetrazol. The most active compound is that of Example 4 and marked activity is shown by the compounds of Examples 3, 35, 42 and 44.

5. Actography The method consists in recording the number of times an animal passes in front of two perpendicular light rays. Mice, either alone or in groups of two, were introduced into activity cages of the Dews type after the compounds under test had been injected intravenously.

The activity was measured after 5, l and minutes. The results are expressed as a percentage of increased or decreased activity with respect to the conwas equal to A of the LD 50, activity decreased by an average of The most active compounds are those of Examples 3 4 and 40 and the compound of Example 35, which reduces activity by 50% during the first 5 minutes.

6. Anti-amphetamine activity, measured by actograp y This activity was evaluated by actography. Mice were given a subcutaneous injection of D-amphetamine tartrate at a dosage of l0 mg/kg. At the same time, the compound under test was administered intravenously to the animals under treatment, while the solvent was given to the control animals. The activity of the mice was measured in the actimeter after 5, l0 and 15 minutes; the injection was made 15 or 30 minutes before measuring time 0.,

The new compounds are relatively antagonistic to the effect of amphetamine on activity, as measured by actography. The results are practically parallel to those obtained for the activity test by actography. The most active compounds are those of Examples 3, 4 and 35.

7. Potentiation of the toxicity of amphetamine on groups of mice Batches of 10 mice grouped together showed agitation after receiving intraperitoneal injections of 15 mg/kg d-amphetamine tartrate. A quarter of an hour later, 30 mg/kg of the compound of Example 2 was intraperitoneally injected. The number of deaths after 8 and 24 hours were noted.

The toxicity of the amphetamine group is considerably potentiated by the compound of Example 30 in doses of 20 mg/kg, and slightly by the compound of Example 2 in doses of 30 mg/kg. The compounds of Examples 38, 40 and 44 are also active.

8. Anti-reserpine activity Mice weighing approximately 20 g were given intraperitoneal injections of 3 mg/kg reserpine. 16 hours later, the compound under test was intravenously injected in doses of 30 mg/kg and the activity was compared with that obtained with imipramine orally administered in doses of 10 mg/kg.

Tests, compared with results on control animals treated with reserpine alone, were made to show the:

1. activity measured by actography.

2. degree of ptosis.

3. the central temperature.

The compounds of Examples 2 and 35 are not very active except in small doses (l/lO of the LD 50) but large doses of compounds of Examples 3, 4 and 44 are required to demonstrate anti-reserpine activity. The compound of Example 35 has an effect both on temperature and on ptosis.

9. Anti-cataleptic activity The test was made on rats which were given intraperitoneal injections of 15 mg/kg prochlorpemazine (Tementil). A state of catalepsy resulted, as could be seen by the crossing of homolateral paws. The compound under test was intraperitoneally injected in doses of mg/kg. The effects were compared with those of amphetamine.

The compounds of Examples 2, 35 and 41 have quite a marked anticataleptic action.

10. Potentiation of toxicity of yohimbine The compounds under test were orally administered to male mice with an average weight of 20 g; 1 hour later the mice were given a subcutaneous injection of 30 mg/kg of yohimbine. The mice were in groups of 10. Next day the numberof deaths was recorded. The results are expressed. as percentage mortality. The object of the test was to show anti-depressant activity.

The most important substances in this respect are the compounds of Example 7, 24 and 34. Compounds of Examples 37, 35 and 45 are less active.

11. Anti-tremorine test The compounds under test were injected intravenously into groups of 5 mice and 20 minutes afterwards 30 mg/kg of tremorine (l,4-dipyrrolidine-2-butyne) was administered intraperitoneally. The amount of salivation and tremors, with respect to control animals which had only been given tremorine, was measured 15, 30 and 60 minutes after the tremorine had been injected. The results are classified by crosses (0 to 5 crosses for tremors and O to 4 crosses for salivation).

Most of the compounds according to the invention antagonise tremors caused by tremorine. The antagonising effect on salivation was most marked.

The compounds of Examples 29, 30, 35, 36, 38, 41, and 45 are considerably antagonistic to tremors and have a marked effect on salivation.

TABLE B Test results for psychotropic activity Com- LDSO in mg/kg, Doses Potentiation of Potentiation Potentiation Activity Anti-amphetamine pound intravenously administered penthiobarbital of chloral of pentetrazol measured by action of injected in in tests, in narcosis narcosis actography Exmice mg/kg I ample I 2 9s 30 t i at 30mg/kg i 3 H 30 i at 40mg/kg -H- i at 40mg/kg at 20mg/kg (50%) at ZOmg/kg 4 80 30 t 70% at 30mg/ +'at and 20 7 kg mg/kg 24 29 45 O 0 30 8O 30 -|l- 0 O 34 I r 35 so 30 i at 30mg/kg o 4+ at mg/kg H at ZOmg/kg at 4Omg/kg 36 so 30 o i at ZOmg/kg at 20rng/kg 37 8O 30 0 0 \l i at ZOmg/kg i at ZOmg/kg 38 50 15 O i i at lOmg/kg 0 at lOmg/kg 40 1 I0 30 i at 40mg/kg 0' H-at 40mg/kg at ZOmg/kg i at 20mg/kg 41 so 30 0 at 20mg/kg i at 20mg/kg 42 so 30 i H at ZOmg/kg 0 44 80 30 i at 40mg/kg 1 :H 1 45 8O 30 0 i i at Smg/kg 0 Com- Toxicity of Anti-reserpine Anti-cateleptic Potentiation of Anti-tremorine pound amphetamine activity activity toxicity of action of group yohimbine Example 2 i- -llat lOmg/kg l-lat IOOmg/kg salivation 0 tremors +4- 3 i at mg/kg 0 at lOmg/kg 0 at SOmg/kg 0 H at SOmg/kg 4 0 at 20mg/kg at IOOmg/kg -l-lsalivation 0 -H- at 40mg/kg tremors -H- 7 -llat 60mg/kg per os 24 -l+- at 60mg/kg per 0s 2 0 0 (at mg/kg)- salivation tremors H- 30 at ZOmg/kg O at 70mg/kg salivation tremors -ll- 34 -ll at BOmg/kg -H- at lOmg/kg at 60mg/kg salivation tremors -ll- 36 0 at 60mg/kg salivation tremors 4+ 37 at 60mg/kg salivation 1- tremors 38 at ISmg/kg 0 at SOmg/kg salivation tremors at ZOmg/kg 0 0 at i 0 salivation -lltremors i 4l 0 at 20mg/kg -l+ at BOmg/kg 0 salivation tremors -ll- 42 0 salivation -H- tremors 44 at 20mg/kg at 40mg/kg d: r I i -H- at 80mg/kg at 60mg/kg salivationH- tremors 4+ In summary, the study of the psychotropic activity of the compounds according to the invention shows that they decrease the normal activity of the animals (actog- Table C;below shows'the comparative activity of 6 compounds according to the invention,'using examples depending on the different tests.' For each test, the

compounds have been'given a mark from 0 to '7', indicating the amount of activity. i

The Table shows-that the compound of Example 2 behaves' like a weak anti-depressant and the compound of Example 40 behaves like a weak tranquilliser. The

compound of Example 44, on the other hand, is relatively excitant. The compounds of Examples 3, 4 and 35 show the aforementioned paradoxical effects to a very marked degree (they depress activity, they have an anti-amphetamine action and potentiate barbiturate sleep, whereas they are excitants in that they potentiate the effects of cardiazol. They also have an anti-reser-I pine effect.

TABLE 1 Comparative activity of 6 derivatives of 4-anilino-pyridine, depending on the tests used. EXAMPLES v v 2 4 3 40 44 35 Tests used Actography 4 4 6 7 2 5 Potentiation of l 7 5 2 5 5 pentetrazol: percentage of tits affected Potentiation of 4 5 2 4 l 7 pentetrazol: percentage of deaths affected Potentiation of 2 6 6 2 2 7 barbiturate narcosis Antiamphetamine 2 6 7 3 1 6 activity Anti-reserpine 7 4 3 0 2 6 activity with with with with with small dose large dose large dose large close smalbdose '0 with with large dose large dose Anti-cataleptic 4 2 g 0 0 l 5 activity Tentative pharmacological Antiweak relatively classification of product, depressant tranquilliser excitant based on total activity relieving substances and amphetamine, which is known to reduce the appetite and cause anxiety.

With regard to the standard anxiety-reducing substances, small non-depressive doses were found to result in an increase in food intake, compared with the control animals. The effect increased and then decreased as the dose was progressively increased. The result was the same for compounds of Examples 2 and 4; the latter compound appeared rather less active.

The results are shown in the following Table D.

TABLE D The effect of the compounds of Examples 2 and 4 and of standard products on the food-intake test on male Charles River rats (substances orally administered, in suspension in a 5% gum arable physiological solution) Products Percentage increase or decrease in food intake, compared with control animals Doses in mg/kg 0.1 0.2 0.5 l 2 5 10 20/25 40/50 100 200 Librium +34% +40.5% +85.5% +6l.5% +31% Equanil +42.5% +47.S% +62% +l6.5%

Valium +47% +40.5% +4% Amphetamine 12% 48.5% 69% Largactil 5.5% +23% +52% 4% 9.5% '22.5% 67.5%

Compound of +64% +44.5% +74% 0 l4% Example 2 Compound of +11.5% +30.5% +40.5%

Example 4 The compounds according to the invention, thereanimals. 50 fore, have an action on the central nervous system such Rats having an initial weight of to g were conditioned to eat for only 2 hours each day but were allowed to drink without restriction.

At least 15 days conditioning was necessary before any experiments were made.

On the day of the test, the animals were divided into batches of 5 and weighed just before the test compound was administered orally, in a 5% suspension of gum arabic in physiological solution, one hour before the food arrived. During the hour, the animals were al- 60 lowed to drink as much as they wished. During the next two hours, they were given their food and were weighed at the end of this period. The increase in weight was calculated and the results were expressed as a percentage increase or decrease in the food taken, compared with the control animals.

The compounds of Examples 2 and 4 were studied for their effect in conjunction with standard anxietythat they are therapeutically indicated to be very interesting anxiety-relieving agents.

lll. Anti-inflammatory action The anti-inflammatory action on rats was tested by three different methods:

a. Oedema of the paw, caused by kaolin This is derived from the method proposed by S. GARCET (Therapie, 1958, 13, pp- 549-555).

0.l5 ml of a 10% kaolin solution suspension in a 9 parts per thousand NaCl solution was injected in the plantar pads of the left back paws of male rats weighing 130 to g. The animals, dividedinto groups of 8 to 10 rats, were treated in the following manner 3 hours after the kaolin had been injected:

Control animals: intraperitoneal injection of 1 ml/ 100 g of 9 parts per thousand NaCl solution.

Group treated with phenyl butazone: 100 mg/kg of this product were injected intraperitoneally, the prod- 27 uct being suspended in 9 parts per thousand NaCl solution 1% carboxymethyl cellulose.

Group treated with the compounds under test: intraperitoneal injection of l ml/lOO g of solutions of suitable concentration.

The volume of the right paw was measured (used for reference) and of the paw treated with the anti-inflammatory agent, at the moment when the substances were administered, and 2, 4 and 24 hours afterwards. The measurement was made with a phethysmograph. In each group the average percentage inflammation of paws injected with kaolin was calculated with respect to paws not injected. Finally, the percentage inhibition of inflammation by the substances tested, in the case of the groups under treatment, was expressed in comparison with the control group.

b. Oedema of paw caused by carrageenine The method used is that described by WINTER, C. A., RISLEY E. A. and NUSS, G. W. (Proc. Soc. Exp. Biol. Med., 1962,11], pp. 544-547).

Groups of 8 rats, identical with the earlier groups, were treated in the following manner:

Control group: intraperitoneal injection of 1 ml/100 g of a 9 parts per thousand NaCl solution;

Group treated with phenyl butazone: 100 mg/kg (1 ml/lOO g) of a suspension of phenyl butazone in 1% carboxymethyl cellulose was administered orally;

Groups treated with the compounds after test: intraperitoneal injection of the compounds in solution in concentrations such that the volume injected was 1 ml/lOO g.

One hour after the phenyl butazone, or immediately after the compounds under test had been injected, 0.05 ml of a 1% suspension of carrageenine in physiological saline solution was injected under the plantar surface of the rats back left paws.

The volume of the paws was measured in the same way as in the previous test and the percentage inhibition of inflammation is given for three different times during the 24 hours following the administration of the inflammatory agent.

0. Oedema of paw caused by serotonine This test, which is designed to show the origin of the anti-inflammatory activity, was suggested by the work of PARRAT and WEST (Brit. J. Pharmacol. 1958, 13, 65) and SFONE and colleague (J. Pharmacol, Experimental. Therap. 1961, 131, 73). Groups of6 male rats were given intraperitoneal injections of the compound under test or the standard substances (6 mg/kg of Largactil). 30 minutes later, 0.05 ml of a solution of serotonine creatine sulphate containing 12 mg serotonine was injected into the rear left paws. The results, which were taken 30 minutes, 1 hour and 3 hours after the serotonine injection, show the percentage inhibition of inflammation compared with the control animals.

Test results for anti-inflammatory activity The tests of oedema of the paw due to kaolin show that the compounds of Examples 7 and 11 have a marked anti-inflammatory action in doses of or mg/kg, whereas the compounds of Examples 24, 3, 31 and have a weaker action.

The oedema due to carrageenine confirms the antiinflammatory action of the compound of Example 7; The compound of Example 40 strongly inhibits the inflammatory process when administered in doses of 100 mg/kg. (The effect of this latter product is as great 28 as that of phenyl butazone orally administered in doses of mg/kg).

The test of oedema due to serotonine shows that the compound of Example 11, when intraperitoneally administered in doses of 30 mg/kg, inhibits more than 50% of the inflammation and has an activity comparable to doses of 6 mg/kg chloropromazine. The compounds of Examples 2 and 7 also have a marked action.

(It is noteworthy that phenyl butazone does not affect inflammation produced by serotonine).

Compounds according to the invention, therefore, are very effective anti-inflammatory agents, more particularly the compounds of Examples 7 and l l.

The compounds according to the invention can be used to treat diseases of the central nervous system. They can be administered orally or parenterally, in normal pharmaceutical forms, inter alia in the form of pills, capsules, solutions and suspensions.

The invention also relates to pharmaceutical compositions containing at least one of the compounds of formula 1 as the active agent in a suitable pharmaceutical excipient.

A suitable formulation is given below for a compressed table containing 20 mg of active substance:

Compound of Example 2 (in the form of 20 mg the salicylate) Polyvinyl pyrrolidone 9.5 mg Maize starch 48 mg Bicalcium phosphate 100.15 mg Talcum 9.5 mg Magnesium stearate 2.85 mg mg Pharmaceutical absolute alcohol q.s.

Clinical study The compound of Example 2 has been used in clinical trials and has been administered in several cases of anxiety depression. The patients were given 3 to 6 tablets per day containing 20 mg of the active compound The results from 6 cases are given below.

patient's health had improved. She was cured in a week and left hospital after 15 davs.

3rd case Mrs. A. D., Aged 34 Diagnosis: anxiophobic neurosis E.E.G.: rapid lines without specific signs Treatment: 5 tablets per day. At the end of 15 days the result was excellent. The patient left hospital. The E.E.G. was normal, without any special sign.

-continued 4th case Miss B. A., aged 23 Diagnosis: emotional immaturity, shown by enuresis and encopresls.

Treatment: 4 tablets per day for l5 days. The patient left hospital on the th day, and was considered cured.

5th case Mrs. C. S.. aged 43.

Diagnosis: depression and attempted suicide E.E.G. normal Treatment: 6 tablets per day for 6 weeks.

The patient left hospital after 2 months,

in a very satisfactory state (the E.E.G. was still normal) 6th case Mr. D. C., aged 31 Diagnosis: anxiety depression, with attempted suicide Treatment: 3, then 4, then 5, then 6 tablets per day 10 da s later: reactivation of conflicts 25th ay: definite improvement. The patient left hospital after 2 months.

A second clinical test was made on the compound in Example 2, administered in the same doses as forthe first series of tests.

These pilot experiments were continued for a year and a half in three different hospitals, on exactly 100 patients. Some patients (47%) had nervous troubles: anxiety neurosis, depression, phobias, etc., while others were psychotic (Schizophrenia, chronic delirium, melancholia, etc.).

The experiments showed that the compound according to the invention is an active substance and easily tolerated. lt relieves anxiety and has anti-depressant properties when given to neurotics.

The results for the 100 patients treated were similar to the earlier results. Good results were obtained for 60% of the serious neuroses. The proportion rises to 71% if depressions are excluded. By good results we mean complete cure or a very great improvement.

The compound is generally less active with psychoses, with the apparent exception of atypical depressions.

The clinical tests show that the compounds according to the invention having the structure defined previously can be successfully used for the treatment of depression or anxiety states.

We claim:

1. An N-amino-substituted 4-anilinopyridine of the formula wherein R is selected from the group consisting of hydrogen,

chlorine, trifluoromethyl, methyl and ethyl;

m is the integer 1 or 2;

A is hydrogen or methyl;

R is alkyl having 1 to 4 carbon atoms;

R is alkyl having 1 to 4 carbon atoms the same as or different from R tetrahydrofurfuryl, or R and R together with the nitrogen atom to which they are attached form morpholino, 2,6-dimethylmorpholino, piperidino, pyrrolidino or piperazino;

or the non toxic acid addition salts thereof.

2. The compound of claim 1, which is N-[3-(N- morpholino)-propyl]-N-(metachlorophenyl)-4- amino-pyridine.

3. The compound of claim 1, which is N-[3-(N- morpholino)-propyl]-N- -(metatrifluoromethylphenyl)-4-aminopyridine.

4. The compound of claim 1, which is N-[2-methyl- 3-(N-morph0lino)-propyl]-N-(metach1orophenyl)-4- amino-pyridine.

5. The compound of claim 1, which is N-[2'-methyl- 3 N-morpholino )-propyl -N-(metatrifluoromethylphenyl)-4-amino-pyridine.

6. A substituted 4-anilinopyridine according to claim 1 in which R and R together with the nitrogen atom to which they are attached is morpholino.

7. A substituted 4-anilinopyridine according to claim 1 in which R and R together with the nitrogen atom to which they are attached is 2,6-dimethylrnorpholino.

' Page 1 of 2 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,928,341 DATED December 23, 1975 |NVENTOR(5) 3 Jean-Louis Delarue and Albert Debarge It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Page 1 of the patent in the ABSTRACT,

l l 3H CH E should read H A :Y H2 t N R 1 )2 1 ,2

Columns 5-6, Table l, Example No. 8, the salt reads "salilcylate" and should read sal lcylate", Columns 5-6, Table I, Example No. 9, the structure Chg CH3 "CH2-CH2-CH2-N/ should read "CH CH -CH -N CH3 \CH3 Page 2 of 2 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,9 DATED December 23, 975 |NV'ENTOR(S) 1 Jean-Louis Delarue and Albert Debarge It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Columns 11-12, Table V] I, Example N0. 35, the structure I H H H 'CH -l lH-CH -N should read CH lH-CH N O CH3 CH3 U Columns 19-20, the Fl rst column of Table A, 'LD5O", F i rst occurrence, should read 'LD5O in mouse"; Columns 23 -24,

Example No. 40 of Table B, under the column For Activity measured by actography, at 20 mg/kg" should read Mat 20 mg/kg" Column 27, l ine 29, "after" should read "under"; Column 30, l ine 38, "-N- should read "-N Signed and Scaled this Twenty-first D f September 1976 [SEAL] Arrest.

RUTH C. MASON Atresting Officer C. MARSHALL DANN Commissioner vj'larenls and Trademarks 

1. AN N-AMINO-SUBSTITUTED 4-ANILINOPYRIDINE OF THE FORMULA
 2. The compound of claim 1, which is N1-(3''-(N-morpholino)-propyl)-N1-(metachlorophenyl)-4-amino-pyridine.
 3. The compound of claim 1, which is N1-(3''-(N-morpholino)-propyl)-N-1-(metatrifluoromethylphenyl)-4-amino -pyridine.
 4. The compound of claim 1, which is N1-(2''-methyl-3''-(N-morpholino)-propyl)-N1-(metachlorophenyl)-4-amino -pyridine.
 5. The compound of claim 1, which is N1-(2''-methyl-3''-(N-morpholino)-propyl)-N1-(metatrifluoromethylphenyl)-4 -amino-pyridine.
 6. A substituted 4-anilinopyridine according to claim 1 in which R1 and R2 together with the nitrogen atom to which they are attached is morpholino.
 7. A substituted 4-anilinopyridine according to claim 1 in which R1 and R2 together with the nitrogen atom to which they are attached is 2,6-dimethylmorpholino. 